Repeated blood transfusions can lead to formation of alloantibodies against RBC alloantigens, antigens on the RBC surface capable of inducing antibody formation in individuals who lack the particular antigen. These RBC alloantibodies increase the risk of hemolytic transfusion reactions and make it difficult to find compatible RBCs for future transfusions. However, the mechanism(s) of how RBC alloantigens induce alloantibodies and the potential pathways responsible for RBC clearance following incompatible transfusions remain poorly understood. The KEL glycoprotein is one of the most immunogenic RBC alloantigens and is also one of the most common alloantigens implicated in hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. Therefore, we developed a mouse model that expresses the human KEL glycoprotein specifically on murine RBCs to understand the factors that contribute to the development and consequences of RBC-induced alloantibody formation. In preliminary results, we found that transfusion of KEL RBCs into KEL immunized C57BL/6 (wild-type) recipients results in a rapid clearance phase, followed by an abrupt change in clearance kinetics, such that the remainder of the KEL RBCs develop resistance to further antibody-mediated clearance. KEL RBCs transfused into immunized recipients displayed significant alterations to the KEL antigen that paralleled the development of RBC resistance, suggesting a role of antigen modulation in the protection of RBCs from additional antibody-mediated removal. Given the potential involvement of complement not only in facilitating antibody-mediated clearance, but also in antigen modulation, we examined the potential role of complement in this process. We found that although KEL antigen levels decrease following transfusion of incompatible KEL RBCs in wild-type mice, KEL expression levels remain unaltered in immunized complement component 3 (C3) knockout KO mice, strongly suggesting that complement may facilitate antigen modulation. Given the ability of anti-KEL antibodies to engage complement and the role of C3 in enhancing antibody formation to other antigens, we examined the potential impact of complement in the development of anti-KEL antibodies following KEL RBC transfusion. In contrast to previous studies, we found that transfusion of KEL RBCs into C3 KO mice actually resulted in a significant increase in anti-KEL antibody formation. Given the ability of C3 to modulate the KEL antigen following incompatible transfusion and the increased levels of anti- KEL antibody that form following transfusion into C3 KO recipients, we hypothesize that complement deposition may mask the KEL antigen from immunologic recognition following incompatible RBC transfusion and reduce the ability of the adaptive immune system to efficiently recognize and therefore respond to the KEL antigen. These fundamental studies will not only define the role of complement in KEL RBC clearance and alloimmunization, but will also provide novel insight into potential therapeutic strategies designed to combat the deleterious effects of RBC alloimmunization.